Differential effects of d- and l-amphetamine on mouse-killing behavior in rats.

Muricidal behavior in rats was selectively antagonized by both the d- and the l-isomer of amphetamine. However, d-amphetamine was approximately 8 times as potent as l-amphetamine as an inhibitor of mouse killing. The results of this study suggest that amphetamine antagonizes muricidal behavior in rats primarily via noradrenergic mechanisms. In addition, these results, as well as those in previous reports, imply that agents which modify the level of activity at central noradrenergic receptors may significantly alter the mouse-killing response of rats.     

Behavioural changes during withdrawal from desmethylimipramine (DMI)

Amphetamine anorexia in rats was potentiated by acute pretreatment with the tricyclic antidepressant desmethylimipramine (DMI), but was not significantly different from controls following chronic DMI pretreatment. During withdrawal from DMI, amphetamine anorexia was attenuated after 2 weeks or 2 months pretreatment, but not after 1 week of treatment. The locomotor stimulant and stereotypy inducing effects of amphetamine were slightly enhanced during withdrawal from chronic DMI. The results are discussed in relation to known neurochemical actions of DMI.     

Possible peripheral adrenergic and cholinergic mechanisms in pseudoconditioning

Buzzers and shocks were presented in random sequence and with no temporal association to rats in a shuttle-box, so that they performed pseudoconditioned barrier-crossing responses to the buzzer. Performance of these responses was enhanced by amphetamine and tyramine. The adrenergic blocking agents yohimbine and dibenamine, though ineffective on their own, antagonized the action of amphetamine and tyramine. Hexamethonium and methylatropine, also ineffective by themselves, potentiated the effect of amphetamine but not that of tyramine. Eserine depressed the performance of pseudoconditioned responses when given alone, and it antagonized the stimulant action of both amphetamine and tyramine. The results suggest that amphetamine and tyramine enhance pseudoconditioning through activation of a peripheral adrenergic mechanism and that amphetamine, in addition, triggers an opposing cholinergic mechanism, also peripheral, from which it can be released by the anticholinergic agents hexamethonium and methylatropine. The depressant action of eserine can also be explained by activation of the cholinergic mechanism.     

Nicotine and amphetamine acutely cross-potentiate their behavioral and neurochemical responses in female Holtzman rats

Rationale  Psychostimulants are often used in close temporal proximity to nicotine and have been reported to enhance acutely nicotine’s desirability in humans. Objective  To investigate the acute associations between amphetamine and nicotine, we examined the potentiative interactions between clinically relevant, low doses of these drugs on locomotor activity, and dopamine overflow in the rat. Materials and methods  Locomotor activity was measured by telemetry in the home cage environment, and dopamine overflow was evaluated in striatal slice preparations from female Holtzman rats. Results  When administered simultaneously, nicotine and amphetamine produced a predominantly additive effect on locomotor behavior. However amphetamine, when given 2–4 h before nicotine, strongly potentiated nicotine-induced locomotor activity. Correspondingly, nicotine given 1–4 h before amphetamine robustly enhanced amphetamine-stimulated locomotor activity even when the effects of the nicotine pretreatment dissipated. Acute nicotine pretreatment similarly potentiated the effects of dopamine transporter ligands, cocaine, nomifensine, and methamphetamine but not a direct dopamine receptor agonist. Consistent with the behavioral studies, in vivo nicotine pretreatment exaggerated amphetamine-induced dopamine efflux from rat striatal slices. Likewise, in vivo pretreatment of rats with amphetamine potentiated nicotine-induced dopamine efflux from striatal slices. Direct pretreatment of striatal tissue by nicotine also potentiated subsequent amphetamine-stimulated dopamine overflow, further suggesting that the nicotine-amphetamine interaction occurs at the level of the dopamine terminal. Conclusion  Overall, the present data demonstrate that acute interactions of nicotine and other psychomotor stimulants produce potentiative effects and that these transient interactions may play a role in the frequent co-use and abuse of nicotine and other stimulants.     

Ventricular infusion of norepinephrine and amphetamine: direct versus indirect action

The behavioral hyperactivity produced by intraventricular infusions of norepinephrine in rats is potentiated by pretreatment with 6-hydroxydopamine. Pretreatment with the catecholamine uptake blocker desmethylimipramine does not alter the effect of norepinephrine, which indicates that the potentiation observed after 6-hydroxdopamine is due to an enhancement of receptor sensitivity rather than to a loss of an uptake inactivation mechanism. Intraventricular infusions of d-amphetamine result in behavioral effects which are comparable to those observed following systematically administered amphetamine: (1) increasing doses produce a graded increase in locomotor activity; (2) high doses elicit a pattern of stereotypy; and (3) d-amphetamine is more potent than l-amphetamine in producing these bahavioral effects. The behavioral effects of amphetamine, in contrast to those induced by norepinephrine, appear to be dependent upon the functional levels of brain catecholamines as indicated by the suppression of amphetamine effects following pretreatment with alpha-methyl-p-tyrosine or reserpine. These results provide evidence for a direct mechanism of action for infused norepinephrine and indicate the potential usefulness of norepinephrine-induced activity as an index of alterations in receptor sensitivity.     

GABAergic involvement in motor effects of an adenosine A(2A) receptor agonist in mice

Adenosine A(2A) agonists are known to induce catalepsy and inhibit dopamine mediated motor hyperactivity. An antagonistic interaction between adenosine A(2A) and dopamine D(2) receptors is known to regulate GABA-mediated neurotransmission in striatopallidal neurons. Stimulation of adenosine A(2A) and dopamine D(2) receptors has been shown to increase and inhibit GABA release respectively in pallidal GABAergic neurons. However, the role of GABAergic neurotransmission in the motor effects of adenosine A(2A) receptors is not yet known. Therefore in the present study the effect of GABAergic agents on adenosine A(2A) receptor agonist (NECA- or CGS 21680) induced catalepsy and inhibition of amphetamine elicited motor hyperactivity was examined. Pretreatment with GABA, the GABA(A) agonist muscimol or the GABA(B) agonist baclofen potentiated whereas the GABA(A) antagonist bicuculline attenuated NECA- or CGS 21680-induced catalepsy. However, the GABA(B) antagonists phaclophen and delta-aminovaleric acid had no effect. Administration of NECA or CGS 21680 not only reduced spontaneous locomotor activity but also antagonized amphetamine elicited motor hyperactivity. These effects of NECA and CGS 21680 were potentiated by GABA or muscimol and antagonized by bicuculline. These findings provide behavioral evidence for the role of GABA in the motor effects of adenosine A(2A) receptor agonists. Activation of adenosine A(2A) receptors increases GABA release which could reduce dopaminergic tone and induce catalepsy or inhibit amphetamine mediated motor hyperactivity.     

Catecholamines and self-stimulation: the action of amantadine and its interaction with amphetamine.

The antiparkinsonian drug amantadine HCl caused a dose-dependent depression of electrical self-stimulation, followed by a dose-dependent enhancement. Neither action was correlated with the differential effects of d- and l-amphetamine at different implantation sites. The initial depression was not prevented by pretreatment with anticholinergic or antiserotonergic agents nor by depression of catecholamine (CA) synthesis. The stimulant effects of amantadine and d-amphetamine summated but did not interact, response rates after d-amphetamine being augmented by pretreatment with amantadine except at intervals at which amantadine was by itself depressant. It is concluded that the initial effect of amantadien is caused by impulse-independent release of a pool of intraneuronal CA, causing dissociation between reinforcement signals and the rat's responses. This is followed by amphetamine-like facilitation of impulse-dependent release; the first action depresses performance, the second enhances it.     

Further studies on the long-term depletion of striatal dopamine in iprindole-treated rats by amphetamine

(+) Amphetamine was more potent than (?) amphetamine in causing persistent depletion of striatal dopamine in iprindole-treated rats. This effect of amphetamine was not mimicked by EXP561, a structurally related compound that is more potent than amphetamine as an inhibitor of dopamine uptake. The depletion of striatal dopamine at 1 week after amphetamine injection in iprindole-treated rats was prevented by amfonelic acid, an inhibitor of uptake into dopamine neurons. The depletion of dopamine by amphetamine was prevented when amfonelic acid was given at the same time as amphetamine or as long as 4 hr after amphetamine but not when amfonelic acid was given 24–48 hr after amphetamine. Amfonelic acid antagonized the depletion of dopamine by amphetamine but not the depletion of serotonin by p-chloroamphetamine; fluoxetine antagonized the depletion of serotonin by p-chloroamphetamine but not the depletion of dopamine by amphetamine. Pretreatment with α-methyltyrosine to block dopamine synthesis antagonized the persistent depletion of dopamine by amphetamine, but pretreatment with an inhibitor of monoamine oxidase to increase the dopamine concentration had no effect. The possibility that prolonged release of dopamine from intraneuronal storage granules leads to deleterious effects on dopamine neurons is discussed.     

Amphetamine's locomotor-stimulant and norepinephrine-releasing effects: Evidence for selective antagonism by nisoxetine

A new procedure that allows simultaneous and objective measurement of both locomotor activity and stereotypy in individual mice was used to determine the effects of the selective noradrenergic uptake inhibitor, nisoxetine (Lilly 94939), on amphetamine-induced changes in these behaviors. Amphetamine markedly increased locomotor activity at a dose of 3 mg/kg, while stereotypy was significantly increased at doses of 5.6 mg/kg and above. After nisoxetine (20 mg/kg, 30 min pretreatment), the locomotor-stimulant effect of amphetamine was abolished and its actions on stereotypy were potentiated. The action of nisoxetine was selective in that it did not significantly affect the locomotor activity induced by a moderate dose (56 mg/kg) of morphine. In addition, nisoxetine pretreatment had little affect on the accumulation of ³H-amphetamine in the mouse brain. Biochemically, nisoxetine (10^-6 M) antagonized amphetamine-induced release of ³H-norepinephrine from the mouse cerebral cortex, but not that of ³H-dopamine or ³H-5-hydroxytryptamine from the mouse corpus striatum. The data indicate that nisoxetine selectively antagonizes certain of amphetamine's behavioral and biochemical actions. They are also consistent with the suggestion that amphetamine-induced release of nor-epinephrine is causally related to the locomotor-stimulant action of amphetamine and may inhibit stereotypy produced by the drug.     

Reduced amphetamine lethality following chronic stress

Rats stressed for up to four days by desynchronized sleep deprivation or repeated immersions in cold water showed adrenal gland hypertrophy and thymus gland atrophy. These chronically stressed rats survived markedly longer following a high dose of amphetamine than non-stressed rats. However, the usual finding of enhanced amphetamine lethality when a novel acute stress is paired with amphetamine administration (in previously non-stressed rats) was confirmed.     

Effects of serotonergic manipulations on the behavioral sensitization and disinhibition associated with repeated amphetamine treatment

This study investigated the effects of repeated amphetamine treatment on locomotor activity and behavioral inhibition in the elevated plus-maze, and the influence of serotonin (5-HT) neurotransmission on these behaviors. Acute administration of amphetamine (1.0 mg/kg subcutaneously [SC]) stimulated locomotor activity, which was attenuated by acute citalopram (5.0 mg/kg SC) pretreatment. Repeated daily treatment with amphetamine (15 days) sensitized the rats to the amphetamine-induced locomotor stimulation. Acute pretreatment with the 5-HT precursor l-5-hydroxytryptophan (5-HTP; 25 mg/kg IP) or chronic treatment with the selective 5-HT reuptake inhibitor citalopram (5.0 mg/kg SC, twice daily), did not alter the expression of amphetamine-induced locomotor sensitization. In the elevated plus-maze, animals subjected to repeated amphetamine treatment expressed behavioral disinhibition after amphetamine exposure (1.0 mg/kg SC; -35 min), which was antagonized both by acute 5-HTP and chronic citalopram treatment. In summary, these findings suggest that behavioral sensitization to amphetamine is associated with amphetamine-induced behavioral disinhibition, and that acute 5-HTP as well as chronic citalopram treatment counteract the expression of amphetamine-induced behavioral disinhibition, but not locomotor sensitization. It appears likely that the antagonistic effects of 5-HTP and citalopram on behavioral disinhibition derive from a drug-induced facilitation of brain 5-HT neurotransmission.     

Interactions of caffeine with various amphetamines on rat food consumption and avoidance responding

Pretreatment of rats with caffeine potentiated the actions of the p-chloro- and p-methyl analogues of amphetamine and benzphetamine as depressants of deprivation-induced food consumption, although no such effects were seen with the unsubstituted compounds. Similar caffeine pretreatment completely antagonized the stimulant effect of amphetamine and p-chloroamphetamine on continuous avoidance responding. In contrast, combined dosage of caffeine potentiated the actions of p-methyl-amphetamine, or benzphetamine, drugs normally showing decreased avoidance responding. Caffeine, in combination with benzphetamine, caused a slight decrease in avoidance responding.     

Norepinephrine elevations in cerebrospinal fluid after d- and l-amphetamine.

We continuously collected cerebrospinal fluid (CSF) from the lateral ventricles of monkeys and gave them from 0.1 to 1.0 mg/kg d- or l-amphetamine intravenously. The norepinephrine (NE) content of their CSF had a small circadian rhythm and a large increase after amphetamine. 1.0 mg/kg amphetamine gave a four-fold rise in CSF-NE which remained elevated for 33 h, smaller doses gave proportionately lesser responses. Both d- and l-amphetamine caused similar NE elevations except for minor differences at the highest dose. If there are differences in behavioral effects of moderate doses of d- and l-amphetamine, they are probably not due to a general difference in central NE release from these stereoisomers.     

Effects of lithium on behaviour induced by phencyclidine and amphetamine in rats

d-Amphetamine and phencyclidine (PCP) have both been reported to produce manic-like sequela in humans, effects that are reportedly antagonized by lithium. To test the hypothesis that the acute effects of these drugs in rats may serve as models of mania, the behaviors, induced by d-amphetamine (3 mg/kg) or PCP (5 mg/kg) were quantified on behavioral rating scales subsequent to chronic dietary pretreatment with lithium carbonate or control diet. On day 14 of pretreatment, PCP-induced stereotyped behaviors and ataxia were potentiated in rats receiving lithium (plasma levels 1.0±0.23 mEq/l). PCP-induced locomotor activity was not affected by lithium pretreatment. Stereotypies and locomotion induced by d-amphetamine were also not significantly affected by lithium pretreatment. These results suggest that neither PCP nor amphetamine administered acutely to rats will be useful models to explore the manic-like symptoms produced by these drugs in humans.     

EGYT-2509 a novel neuroleptic agent without extrapyramidal and endocrine side effects

The dibenzodioxazocine derivative EGYT-2509 was effective in neuropsychopharmacological tests characteristic for neuroleptics and antiparkinsonian drugs. It interacted with dopaminergic compounds similarly to chlorpromazine and haloperidol, but in certain tests it showed different activity. Similarly to chlorpromazine and haloperidol it inhibited the lethal effect of amphetamine in grouped mice. The apomorphine-induced stereotypy was potentiated by lower, and antagonized by higher doses of EGYT-2509. The compound did not show cataleptogenic activity and even antagonized the catalepsy evoked by bulbocapnine. The in vitro potency of EGYT-2509 to block dopamine-mediated inhibition of prolactin release was weaker by three orders of magnitude than that of haloperidol. In preliminary human studies it did not affect the plasma prolactin level. It is concluded that EGYT-2509 is a new potential antipsychotic agent with minimal risk of extrapyramidal and endocrine side effects.     

Effect of pretreatment with amphetamine on the interaction between amphetamine and dopamine neurons in the nucleus accumbens

The present study was designed to examine the effect of pretreatment with amphetamine on the ability of amphetamine to release dopamine from slices of the nucleus accumbens and striatum and to stimulate locomotor activity or stereotyped behavior, after direct injection into either the nucleus accumbens or the striatum. Rats were injected twice daily for 5 days with either amphetamine (5 mg/kg, i.p.) or saline. At 33 days after this pretreatment, the release of endogenous dopamine from both regions of the brain in vitro by amphetamine and the changes in behavioral responses to the direct injection of amphetamine into either region were examined. Amphetamine at both 1 and 10 microM stimulated the release of endogenous dopamine from slices prepared from both of the brain areas. The release of dopamine by amphetamine was increased in rats pretreated with amphetamine. Consistent with its ability to stimulate endogenous release of dopamine, amphetamine, when injected into the nucleus accumbens, stimulated locomotor activity, while stereotyped behavior was enhanced when amphetamine was injected into the striatum. However, the locomotor activity and stereotyped behavioral responses to small doses of amphetamine (5, 10 or 25 micrograms) were not significantly greater in amphetamine-pretreated rats, compared to saline-pretreated animals. A greater stimulation of both responses in amphetamine-pretreated rats was only observed when a large dose (50 micrograms) of amphetamine was administered into either the nucleus accumbens or striatum.(ABSTRACT TRUNCATED AT 250 WORDS)     

Anorexigenic effects of d-amphetamine and 1-dopa in the rat

The effect of amphetamine and 1-dopa was compared in 22-hr food- and water-deprived rats. Amphetamine produced marked anorexia, and 1-dopa significantly reduced food intake at 200 mg/kg. Following pretreatment with RO 4-4602, a decarboxylase inhibitor, 100 mg/kg of 1-dopa, a dose that did not significantly affect eating, produced marked anorexia. The anorectic effect of both amphetamine and 1-dopa was antagonized by propranolol, a β adrenergic antagonist. Phentolamine, an a-adrenergic antagonist, potentiated the anorectic effect of amphetamine and 1-dopa. Haloperidol (0.1 mg/kg), a dopamine antagonist, failed to prevent the anorexia due to amphetamine but accentuated that due to 1-dopa. Methysergide, a serotonin antagonist, also failed to prevent the anorexigenic effect of amphetamine. Finally, the administration of 1-dopa with or without peripheral decarboxylase inhibition resulted in more than twice the increase in hypothalamic dopamine levels without significant changes in 5-HT or norepinephrine levels. The data show that the anorexigenic effect of amphetamine and 1-dopa are similar and indicate a functional role for both norepinephrine and dopamine neurons in feeding behaviour in the rat.     

Time course of the development of the enhanced behavioral and biochemical responses to amphetamine after pretreatment with amphetamine

These experiments were designed to examine the time course of development of the enhanced stereotyped behavioral response to amphetamine after withdrawal from chronic pretreatment with amphetamine and to determine whether this time course correlates with that of the enhancement in the amphetamine-induced stimulation of the release of dopamine (DA) from striatal slices. Rats were pretreated with amphetamine (5 mg/kg, i.p.) or saline, twice daily for 5 consecutive days. At 3, 15 and 30 days after withdrawal of the drug the stereotyped behavioral response and the release of endogenous DA from slices of striatum in response to a challenge dose of amphetamine were measured. At all 3 times tested, the stereotyped behavioral response to the challenge dose of amphetamine was enhanced in the rats pretreated with amphetamine, with the greatest degree of enhancement seen at 15 and 30 days after withdrawal of the drug. At these times, the responses were associated with a significant attenuation in the stimulation of locomotor activity produced by the challenge dose of amphetamine, which was probably related to the enhanced stereotyped behavioral response. Amphetamine stimulated the release of endogenous DA from slices of striatum in rats pretreated with saline and amphetamine. However, the release of endogenous DA from slices of rats pretreated with amphetamine was significantly greater than that of saline-pretreated rats at 15 and 30 days after withdrawal of the drug, but not at 3 days after withdrawal. Thus, pretreatment with amphetamine resulted in enhanced behavioral and biochemical responses to amphetamine which increased over time after withdrawal of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)     

Calcium dependence of sensitised dopamine release in rat nucleus accumbens following amphetamine challenge: implications for the disruption of latent inhibition

Repeated amphetamine treatment results in sensitisation both of its behavioural effects, and of its dopamine (DA)-releasing effects on which the former largely depend. Understanding the nature of the sensitised response may help to explain behaviours which emerge only with repeated treatment, such as particular stereotypies and effects on social behaviour in animals, and links between these effects and the emergence of dependence and psychotic symptoms in humans. We show here that a single pretreatment with amphetamine (1mg/kg) is sufficient to sensitise the locomotor response to amphetamine challenge (1mg/kg) 24h later. We have used in vivo microdialysis in the nucleus accumbens in unrestrained rats to demonstrate a corresponding potentiation in the DA response; the marked increase in accumbens dialysate DA following amphetamine (to 427% of basal) was significantly potentiated (to 675% of basal) by the pretreatment, without any alteration in the basal DA. There was also no change in the expected reduction in DA metabolites. Replacement of perfusate calcium by magnesium left the response to acute amphetamine challenge substantially unaffected, as expected from previous reports; however, the potentiation of the DA response by amphetamine pretreatment was prevented. Similarly the potentiated response was attenuated by administration of ondansetron, a 5HT-3 antagonist, (0.01mg/kg) before each amphetamine treatment. The ability of amphetamine to disrupt latent inhibition (L1), which is also disrupted in acute schizophrenia, has been suggested to provide a model of schizophrenia linking underlying cognitive deficits with the DA theory of the disorder. Since LI is disrupted by two systemic administrations of amphetamine 24h apart, but not by one, the present results are consistent with the concept that it is the calcium, and hence impulse, dependence of increased accumbal DA release, rather than its magnitude, which is critical for the disruption of LI.     

Anticholinesterase (DFP) toxicity antagonism by chronic donepezil: a potential nerve agent treatment

Animal studies exploring the antagonism of irreversible cholinesterase inhibitors (i.e. nerve agents) such as soman and sarin have shown that pretreatment with the reversible centrally acting cholinesterase inhibitor, physostigmine, alone or in conjunction with the centrally acting anticholinergic drug, scopolamine, antagonizes the lethality and toxicity of these agents. This study evaluated the effects of pretreatment with the oral cholinesterase inhibitor and anti-Alzheimer's agent, donepezil (Aricept) on the hypokinetic, hypothermic and diarrhea-inducing effects of the irreversible long-acting cholinesterase inhibitor, diisopropylfluorophosphate (DFP) in adult Sprague-Dawley rats. Donepezil (2 mg/kg), given acutely (30 min pretreatment) or chronically (10 daily treatments), significantly antagonized the hypothermia, hypoactivity and diarrhea induced by DFP (1.25 mg/kg) administration. The effects were most prominent 4 and 6 h after the injection of DFP and some protection was observed even when the last treatment of the chronic donepezil protocol was given 24 h before the DFP injection. Although these phenomena are not the same as lethality, they may be parallel phenomena, and our results may have therapeutic implications for the treatment of nerve agent toxicity.